Differing hepatotoxicity and lethality after subacute trichloroethylene exposure in aqueous or corn oil gavage vehicles in B6C3F1 Mice

Merrick, B. Alex; Robinson, Merrel; Condie, Lyman W.

doi:10.1002/jat.2550090105

Cited by 19 publications

(12 citation statements)

References 24 publications

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“…TCE also caused increased liver weight. The latter was expected, due to the reversible cellular hypertrophy reported following exposure to this solvent (15,30). TCE has been reported to cause altered perception, cardiac arrhythmias, hearing loss, and loss of nerve function in man and animals (4,6,16,22,30), but we did not observe any of these changes.…”

Section: Resultsmentioning

confidence: 82%

Toxicosis Associated with Dual Oral Exposure of Rats to Lead and Trichloroethylene

2001

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To determine if additive or synergistic toxic effects would occur, adult male rats were exposed orally to lead carbonat e (2,000 mg/kg) for 9 days before trichloroethylen e (TCE), 2,000 mg/kg, was given concurrentl y for an additional 7 days. Comparisons were made with groups of vehicle-treated rats and rats given only lead or only TCE. Potential neurotoxicity was evaluated by using the Functional Observationa l Battery (FOB) recommended for neurotoxicity screening. Rats were sacri ced on day 16, and brain, testes, spleen, kidney/adrenals, heart, and liver weighed and observed for pathological changes. Results of the FOB indicated that lead carbonate was more responsible than TCE for changes observed. Additive or synergistic neurotoxicities were not noted. Histological examination of the kidney from lead-treated rats revealed inclusions, an increased incidence of coagulated proteins, and tubular dilation that was generally more severe in the medullary segments. Gastric and testicular necrosis were found in rats given lead carbonate both with and without TCE (15/20 and 6/20 treated, respectively). The results suggest that, even when given concurrently, the toxicities of lead carbonate and TCE are expressed only as though one toxicant was given.

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Section: Resultsmentioning

confidence: 82%

Toxicosis Associated with Dual Oral Exposure of Rats to Lead and Trichloroethylene

2001

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“…As mentioned in die Introduction, Emulphor has become one of the most common products used in toxicology for formulating aqueous emulsions of highly lipophilic chemicals. Emulphor has been utilized by a number of research groups studying the oral toxicity of halocarbons, including CCL,, CHCI3 and TCE Sanders et al, 1982;Merrick et al, 1989;Borzelleca et al, 1990;Sanzgiri et al, 1995). No toxicity was reported by any of these investigators in their vehicle control groups, but experimental conditions, species, toxicity indices, and Emulphor concentrations varied.…”

Section: Discussionmentioning

confidence: 99%

“…Chloroform (CHC1 3 ) (Bull et al, 1986) and carbon tetrachloride (CCL,) (Condie et al, 1986) were both more hepatotoxic to mice when given for 90 days in corn oil than when given in an aqueous Tween suspension. The same was shown to be true for trichloroethylene (TCE) (Merrick et al, 1989). When CHC1 3 was given by corn oil gavage in a carcinogenicity bioassay, it produced a high incidence of hepatocellular carcinoma in B6C3FI mice (NCI, 1976).…”

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confidence: 82%

“…Emulphor has been reported to be cytotoxic in vitro, at concentrations >0.125%, when added to isolated hepatocytes (O'Hara et al, 1989). Although low doses of Emulphor do not appear to be hepatotoxic or to alter the hepatotoxic potency of halocarbons in vivo (Merrick et al, 1989;Kim et al, 1990a;Borzelleca et al, 1990), a comprehensive evaluation of the ability of a wide range of doses of Emulphor to alter the kinetics or toxicity of a halocarbon or other VOC could not be located in the literature.…”

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confidence: 99%

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Effect of Emulphor, an Emulsifier, on the Pharmacokinetics and Hepatotoxicity of Oral Carbon Tetrachloride in the Rat

SANZGIRI¹,

BRUCKNER²

1997

Toxicol Sci

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Emulphor, a polyethoxylated vegetable oil, is now being used widely to incorporate volatile organic compounds (VOCs) and other lipophilic compounds into aqueous solutions for biochemical, pharmacokinetic, and toxicological studies. Previous work in this laboratory demonstrated that 0.25% Emulphor did not alter the kinetics or hepatotoxicity of low doses of CCL, compared to when the halocarbon was given to rats orally in water. The present study was undertaken as there was concern that higher concentrations of Emulphor (necessary to maintain lipophilic VOCs in stable aqueous emulsions for extended periods) might alter the VOCs' absorption, disposition, and/or toxidty. Dosages of 10 and 180 mg CCU/kg bw were given, as an aqueous emulsion using 1, 2.5, 5, or 10% Emulphor, by gavage to fasted male Sprague-Dawley rats. Serial microsamples of blood were collected from an indwelling cannula in unanesthetized, freely moving rats at intervals of 2-60 min for up to 12 hr. The samples' CCL, content was measured by headspace gas chromatography. Thereby, it was possible to obtain blood CCL, concentration-versus-time profiles. Animals were euthanized 24 hr postdosing and blood was collected for measurement of serum enzymes as indices of hepatotoxicity. No toxicologically significant differences in pharmacokinetic parameters as a function of Emulphor concentration were found. Similarly the hepatotoxic potency of 10 and 180 mg/kg CCL,, as reflected by elevation in serum enzyme activities, did not vary significantly with the concentration of Emulphor utilized. Hence, it can be concluded that Emulphor, in concentrations as high as 10% (equivalent to 260 mg Emulphor/kg bw) in aqueous emulsions, does not significantly affect the absorption, disposition, or acute hepatotoxicity of CCL, in male Sprague-Dawley rats, o iw sod«y of To

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“…Liver effects in animals are the best-characterized noncancer end point associated with TCE (2). Numerous measures of effects have been reported including alterations in liverto-body weight ratio (LW/BW) (25,(54)(55)(56)(57)(58)(59)(60)(61), largely due to hypertrophy and some hyperplasia (54,58), peroxisome proliferation, altered serum levels of liver enzymes, and histopathologically observable changes including necrosis. Some of these effects (e.g., LW/BW, peroxisome proliferation) are not typically considered adverse effects by themselves, while others are (e.g., histopathology).…”

Section: Selection Oforal Studiesmentioning

confidence: 99%

Evaluating noncancer effects of trichloroethylene: dosimetry, mode of action, and risk assessment.

Barton

Clewell

2000

Environ Health Perspect

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Alternatives for developing chronic exposure limits for noncancer effects of trichloroethylene (TCE) were evaluated. These alternatives were organized within a framework for dose-response assessment-exposure:dosimetry (pharmacokinetics):mode of action (pharmacodynamics):response. This framework provides a consistent structure within which to make scientific judgments about available information, its interpretation, and use. These judgments occur in the selection of critical studies, internal dose metrics, pharmacokinetic models, approaches for interspecies extrapolation of pharmacodynamics, and uncertainty factors. Potentially limiting end points included developmental eye malformations, liver effects, immunotoxicity, and kidney toxicity from oral exposure and neurological, liver, and kidney effects by inhalation. Each end point was evaluated quantitatively using several methods. Default analyses used the traditional no-observed adverse effect level divided by uncertainty factors and the benchmark dose divided by uncertainty factors methods. Subsequently, mode-of-action and pharmacokinetic information were incorporated. Internal dose metrics were estimated using a physiologically based pharmacokinetic (PBPK) model for TCE and its major metabolites. This approach was notably useful with neurological and kidney toxicities. The human PBPK model provided estimates of human exposure doses for the internal dose metrics. Pharmacodynamic data or default assumptions were used for interspecies extrapolation. For liver and neurological effects, humans appear no more sensitive than rodents when internal dose metrics were considered. Therefore, the interspecies uncertainty factor was reduced, illustrating that uncertainty factors are a semiquantitative approach fitting into the organizational framework. Incorporation of pharmacokinetics and pharmacodynamics can result in values that differ significantly from those obtained with the default methods. Key words: benchmark dose, chloral, developmental toxicity, dose-response assessment, kidney toxicity, liver toxicity, neurotoxicity, PBPK modeling, A consistent framework has been evolving for analyzing dose-response information that reflects relevant biological processes (6,7). Depending on the availability of information, different methods can be used within the overall exposure-dosimetry modeof-action response framework (Figure 1). All dose-response assessment methods begin with the identification of a toxic effect and then estimate acceptable exposure levels protective of human health (7-10). The default approach, in the absence of information, identifies a no-observed adverse effect level (NOAEL) or lowest-observed effect level (LOAEL) and then makes assumptions about mode of action and dosimetry embodied in standard uncertainty factors and adjustments to continuous or daily exposure (11)(12)(13)(14). An This article is part of the monograph on Trichloroethylene Toxicity.

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Differing hepatotoxicity and lethality after subacute trichloroethylene exposure in aqueous or corn oil gavage vehicles in B6C3F1 Mice

Cited by 19 publications

References 24 publications

Toxicosis Associated with Dual Oral Exposure of Rats to Lead and Trichloroethylene

Toxicosis Associated with Dual Oral Exposure of Rats to Lead and Trichloroethylene

Effect of Emulphor, an Emulsifier, on the Pharmacokinetics and Hepatotoxicity of Oral Carbon Tetrachloride in the Rat

Evaluating noncancer effects of trichloroethylene: dosimetry, mode of action, and risk assessment.

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